Method for optimizing ciprofloxacin treatment of anthrax-exposed patients according to the patient&#39;s characteristics

ABSTRACT

The present invention relates to a method for optimizing ciprofloxacin treatment of anthrax-exposed patients according to the patient&#39;s characteristics. More particularly, the invention optimizes the survival outcome of a ciprofloxacin treatment for an anthrax-exposed patient, with the ciprofloxacin dose regimen adjusted according to the patient&#39;s characteristics, including age, body weight, gender, and renal function.

CROSS-REFERENCE TO RELATED APPLICATIONS

Reference Cited: U.S. Pat. No. 4,670,444; June, 1987; Grohe et al,;514/300.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a method for optimizing ciprofloxacintreatment of anthrax-exposed patients according to the patient'scharacteristics. More particularly, the invention optimizes the survivaloutcome of a ciprofloxacin treatment for an anthrax-exposed patient,with the ciprofloxacin dose regimen adjusted according to the patient'scharacteristics, including age, body weight, gender, and renal function.

2. Description of the Related Art

The effectiveness of ciprofloxacin treatment for anthrax maysignificantly rely on the adequacy of the antibiotic regimen. Theregimens of ciprofloxacin currently recommended for treating anthrax arebased only on animal survival data and minimum pharmacokineticinformation [Physician's Desk Reference, 2001]. Due to the lack of humandata reviewed in the prior art, a fixed regimen has been recommended forall patients, namely 500 mg twice daily oral dose.

Even with the fact that the effectiveness of ciprofloxacin against mostother infectious organisms is over 80% [Physician's Desk Reference,2001] at the recommended doses, the survival rate of anthrax patientstreated with the drug remains relatively low (50˜60% in the US 2001outbreak [CDC MMWR Weekly, 2001]).

Thus, it is desirable to improve and optimize the currently recommendedciprofloxacin regimen in order to increase the patient survival rate. Itis therefore necessary to determine the survival rates ofanthrax-exposed patients treated with different ciprofloxacin regimensand select the optimal treatments. One possible approach to obtain thesurvival data is to conduct human experiments to investigate theeffectiveness of various dose regimens in different patient populations.However, this approach is not practical due to the ethical reason.

3. Information Disclosure

Ciprofloxacin and its quinolone family are a series of potentantimicrobial agents with a broad spectrum of antimicrobial activities.The quinolone family is active against a variety of human and veterinarypathogens, including both gram-positive and gram-negative bacteria.Ciprofloxacin is disclosed in U.S. Pat. No. 4,670,444, issued Jun. 2,1987 to Bayer Aktiengesellschaft.

BRIEF SUMMARY OF THE INVENTION

The present invention seeks to overcome the drawbacks inherent in theprior art by providing new methods for improving and optimizing theciprofloxacin regimen for treating anthrax-exposed patients.

Therefore, one object of the present invention is to provide a method tooptimize the survival rate of ciprofloxacin treatment for anthrax indifferent patient populations.

It is known that a complete bacteria eradication by ciprofloxacinusually occurs within several days after the initiation of theantibiotic treatment. Therefore, during the first few days of theantibiotic treatment, the patients may remain culture-positive. Sincethe deaths of the patients infected with anthrax are associated with thepresence of the bacteria in the patient's body, it is plausible that themortality rate of the ciprofloxacin-treated and yet culture-positivepatients is similar to the mortality rate of the controlled patients whoreceive no effective treatment, if significant amounts of anthraxbacteria remain in patients from both treated and controlled groups.

Therefore, the mortality rate of the ciprofloxacin-treated patients canbe estimated from the mortality rate of the controlled patients, if theduration of exposure to the anthrax bacteria in the former can bedetermined from the bacteria eradication rate of the ciprofloxacinregimen.

It has been unexpectedly discovered, during the investigations of themortality rate of various ciprofloxacin regimens for treatinganthrax-exposed patients, that the mortality rate among patients ishighly variable depending on the patient characteristics. It has alsobeen discovered that, the mortality rate of anthrax in certain patientpopulations can be reduced by up to 2 folds, compared to the treatmenteffects of the currently recommended regimens, if the patients aretreated with an optimized ciprofloxacin regimens. It has further beendiscovered that the optimal ciprofloxacin regimen for treating anthraxis between 625 mg to 1500 mg twice daily oral dose for some patientpopulations and the precise optimal regimen is dependent on thepatient's characteristics.

The mortality rate is equal to (1−survival rate).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the survival curves of patients in the Sverdlovsk anthraxoutbreak in 1979 [Meselson et al, 1994], patients in the US bioterrorismattacks in 2001 [CDC MMWR Weekly, 2001], and monkey in the control groupof an animal experiment [Friedlander et al, 1993].

FIG. 2 shows the distribution of onset-to-treatment time in theSverdlovsk [Walker, 2000] and US patients [CDC MMWR Weekly, 2000].

FIG. 3 shows the bacteria eradication rate after 1 to 10 days ofciprofloxacin treatment as a function of AUC/MIC values, independent ofthe type of organisms [Forrest et al, 1993(b)].

FIG. 4 shows the estimated distribution of AUC/MIC (based on populationmodel described by Equation 3) for a population with age=30 year andbody weight=70 Kg, following 500 mg bid ciprofloxacin oral doses.

FIG. 5 shows the estimated overall survival rates on day 10 afterdisease onset in a typical patient population (age=40-79 year andBW=50-90 KG), compared with the historical data. The historical dataconsist of the overall survival data of the victims in the USbioterrorism attacks (FIG. 1) with the average onset-to-treatment time=4days (FIG. 2); the overall survival rate of the patients in theSverdlovsk outbreak (FIG. 1), assuming no effective treatment was given(onset-to-treatment>8 days); the survival rate of monkeys [Friedlanderet al, 1993] with comparable ciprofloxacin plasma concentration(treatment initiated on day 0); and the 6-point running average of theUS data.

FIG. 6 shows the estimated overall survival rates on day 10 afterdisease onset in patients with age equal to 30 year, body weight rangingfrom 60 to 130 Kg, following various twice daily (bid) dose regimens ofciprofloxacin initiated from 0 to 5 days after the disease onset.

DETAILED DESCRIPTIONS OF THE INVENTION

The present invention provides new methods for optimizing thetherapeutic outcomes of ciprofloxacin treatment for anthrax-exposedpatients according to the patients' characteristics. The invention alsoprovides new methods for selecting effective ciprofloxacin treatmentsand targeting the survival outcomes of ciprofloxacin treatment foranthrax-exposed patients according to the patients' characteristics.

A. Anthrax and Its Treatments

Anthrax is a zoonotic infection that has been recognized as a humandisease for thousands of years. Cutaneous, gastrointestinal, andinhalational forms of infection with Bacillus anthracis have beentraditional associated with agricultural or industrial exposures. Therehave been several documented anthrax outbreaks in the recent history,such as those in Sverdlovsk 1979 [Meselson et al, 1994] and in the US2001 [CDC MMWR Weekly, 2001]. This invention will be applied to the mostlethal form of anthrax infections—inhalation.

Ciprofloxacin is currently recommended as one of the treatments foranthrax. The effectiveness of the treatment has been previouslydemonstrated primarily based on an experiment conducted in RhesusMonkeys [Friedlander et al, 1993; Kelly et al, 1992; Physician's DeskReference 2001]. In the animal experiment, groups of 10 monkeys wereexposed to a lethal aerosol dose of Bacillus anthracis spores. One dayafter the exposure, the animals were treated with the antibioticcontinuously for 30 days. The antibiotic regimen provided sufficientprotection to the animals while on therapy. The peak and trough plasmaconcentrations of the antibiotics were obtained from the animals aftermultiple doses [Kelly et al, 1992]. The required dose regimens ofciprofloxacin [Physician's Desk Reference, 2001] in human for treatinganthrax were estimated so that the regimens will produce similar plasmadrug concentration in human to those in the animal experiment.

In the previous art, human survival data of anthrax-exposed patients,human pharmacokinetics, and human ciprofloxacin pharmacodynamicsinformation have not been fully utilized to optimize the therapeuticoutcomes of ciprofloxacin treatment. Even with the fact that theeffectiveness of ciprofloxacin against most other infectious organismsis over 80% [Physician's Desk Reference, 2001] at the recommended doses,the survival rate of anthrax patients treated with the drug remainsrelatively low (50˜60% in the US 2001 outbreak [CDC MMWR Weekly, 2001]).Since anthrax is a fatal disease, dose adjustment based on patientcharacteristics may have clinically significant impacts on the patientsurvival.

The inventor has developed novel methods for predicting the survivalrate of patients infected with anthrax as a function of the patientcharacteristics. The methods utilizes the existing humanpharmacokinetics and pharmacodynamics data of ciprofloxacin, and thesurvival rate of patients in an anthrax outbreak in Sverdlovsk 1979. Themethods first estimates the percentage of patients with complete anthraxbacteria eradication as a function of time after treatment initiation,with the eradication rate stratified by the pharmacodynamic marker,AUC/MIC. The time to bacteria eradication is then correlated to thepatient survival rate based on documented human survival data followingthe historical anthrax outbreak. The pharmacodynamic marker is highlyvariable among patients, influenced by the patient characteristics, suchas body weight, renal function, age, and gender. Another critical factoraffecting the survival rate is the disease onset-to-treatment time. Themethod adequately predicted the overall survival rate of the victims inthe recent bioterrorism attacks in the US 2001.

The present invention was developed from a series of investigationsbased on the aforementioned new methods. As a result of theseinvestigations, it was unexpectedly discovered that certain doseregimens of ciprofloxacin provide significantly better effectivenessthan the previously recommended 500 mg twice daily regimen for treatinganthrax in some patient populations. These investigations are describedin the following sections (Sections B-H).

B. Survival Rate of Controlled Patients Treated with Placebo or InactiveTreatments or Receiving no Treatment

An investigation determined the survival rate of the controlled patientswho contract anthrax and receive no effective treatment, with thesurvival rate as a function of time after disease onset.

The survival rate is defined as the percentage or the ratio of thepatients who survive a disease, relative to the total number of patientscontracting the disease. The mortality rate is usually defined as thepercentage or the ratio of the patients who die from a disease, relativeto the total number of patients contracting the disease. Thus, themortality rate is equal to (1−survival rate).

Survival data of human and monkeys exposed to anthrax are available inthe literature (FIG. 1). The survival rates of anthrax-exposed Rhesusmonkeys were reported [Friedlander et al, 1993] for those treated with125 mg bid ciprofloxacin and placebo. In this study, groups of 10monkeys were exposed to a lethal aerosol dose of Bacillus anthracisspores. One day after the exposure, the animals were treated with theantibiotics or placebo continuously for 30 days. The group of animaltreated with ciprofloxacin were adequately protected from the disease,while the survival rate was 10% for the control group 10 days after theanthrax exposure (FIG. 1).

During the Sverdlovsk anthrax outbreak in 1979 [Meselson et al, 1994],there were 79 documented patients infected with inhalational anthrax,and out of these 79 patients, 68 died [Inglesby et al, 1999]. Out of the68 deaths, 50 had documented onset-to-death time. The survival rates arepresented in FIG. 1. The onset-to-treatment time is available in 21patients [Walker, 2000], and it is plotted in FIG. 2.

There were 11 confirmed inhalational anthrax cases in the bioterrorismattacks in the US from Oct. 1^(st) to Nov. 30^(th), 2001 [CDC MMWRWeekly, 2000]. Five out of the 11 patients died before December 31. Theonset-to-death time is available in all patients [CDC MMWR Weekly,2000]. The survival rate of these US patients is shown in FIG. 1. Theonset-to-treatment time is available in all US patients and thedistribution is shown in FIG. 2.

It appears that the survival rate of the patients in the Sverdlovskoutbreak was similar to or slightly lower than the survival rate of themonkeys in the controlled group of the 1993 experiment. The Sverdlovskpatients were reportedly treated with penicillin, cephalosporin,chloramphenicol, anti-anthrax globin, corticosteroids, osmo-regulatorysolutions, and artificial respiration. However, the exact dose regimenswere not clearly described in the original paper [Meselson et al, 1994].Out of the 68 deaths in the Sverdlovsk outbreak, 21 had documentedonset-to-treatment time (FIG. 2), which did not show any significanttreatment delay compared to the US data. The overall mortality rate ofthe Sverdlovsk patients (86%) was also similar to the occupationallyacquired cases in the US (89%) [Inglesby et al, 1999], the later mostlyoccurring before the advent of antibiotics. Based on the fact thatsurvival rate in the Sverdlovsk outbreak was similar to those of theanimal controlled group and to the occupationally acquired cases withoutantibiotic treatment, it is apparent that the antibiotic treatment givento the Sverdlovsk patients was ineffective. Thus, the survival curvefrom the Sverdlovsk patients was treated as one obtained from aninactive controlled group.

The survival rate from the controlled patients can be expressed by thefollowing empirical equation:

Survival rate up to day i=S _(i)%  (1)

where day i is the day after the disease onset, which ranges from 1 to10 days. Day 0 is the day of disease onset.

The overall survival of the US patients was 55% up to Dec. 31, 2001.This survival rate is significantly higher than that of the Sverdlovskpatients [Meselson et al, 1994], but lower than theciprofloxacin-treated animals (90% for intend-to-treat) [Friedlander etal, 1993]. It appears that at least ciprofloxacin was given to thesepatients, perhaps in combination of other antibiotics [CDC MMWR Weekly,2000].

C. Correlation Between Bacteria Eradication Rate and PharmacodynamicMarker of Ciprofloxacin

Another investigation utilized the pharmacodynamic marker ofciprofloxacin to predict the anthrax bacteria eradication rate inanthrax-exposed patients who receive ciprofloxacin treatments.

A number of pharmacodynamics biomarkers for the efficacy of antibioticshave been defined in the literature [Sanchez-Navarro et al, 1999; Hyattet al, 1995] that consider microbiological and pharmacokineticparameters together. These biomarkers are intended for evaluating thepotential efficacy of antimicrobial treatments that is correlated to thevalues of the biomarkers. The pharmacodynamic biomarkers most studiedand recommended as predictors of the response to anti-infectivetherapies include:

Cmax/MIC: The ratio of the maximum plasma drug concentration to theminimum inhibitory concentration.

AUC/MIC: The ratio of the area under the plasma drug concentration curveto the minimum inhibitory concentration.

Tmic: Time for which the plasma drug concentration exceeds MIC.

AUC_(>mic): Area under the drug concentration curve for which theconcentration exceed MIC.

PK variable: Other pharmacokinetic parameters that are derived from theantibiotic plasma concentration.

The AUC/MIC ratio of ciprofloxacin has been correlated to the bacteriaeradication rate [Forrest et al, 1993(b)]. The inventor contemplatesthat the bacteria eradication rate can be an influential parameter forsuccessful treatments of anthrax, since the survival rate ofanthrax-culture-positive patients reduces drastically as a function oftime. An adequate AUC/MIC ratio in anthrax-exposed patients shouldprovide rapid bacteria kill and prevent fatality that may take placewithin days due to the toxin excreted by the organism. The relativelylow survival rate (50˜60% in the US 2001 outbreak) of anthrax patientstreated with ciprofloxacin is in part due to the delay of treatments andthe fact that a complete bacteria eradication at low AUC/MIC ofciprofloxacin may take more than 10 days [Forrest et al, 1993(b)].However, most of the anthrax-exposed patients died within 10 daysfollowing the disease onset [Meselson et al, 1994]. The between-subjectvariability in ciprofloxacin pharmacodynamic markers may also play arole in the low survival rate, as the AUC/MIC ratio following the sameregimen may be sufficient to produce anthrax bacteria kill in somepatients but sub-optimal in others.

The bacteria eradication rate is defined as the percentage or the ratioof the patients that become culture-negative, relative to the initialtotal number of patients infected with the bacteria. The bacteriaeradication rate usually increases with the duration of an antibiotictreatment. The bacteria eradication rate can be obtained from humanstudies [Forrest et al, 1993(b)], animal studies [Firsov et al, 1997],or in vitro studies [McGrath et al, 1994].

The reported MIC of ciprofloxacin against anthrax varies from 0.06 μg/mLto 0.08 μg/mL [Friedlander et al, 1993; Physician's Desk Reference,2001]. A mid point of 0.07 μg/mL was adopted in the models used by thepresent invention. It has been demonstrated [Forrest et al, 1993(b);MacGowan et al, 1999; Firsov et al, 1997] that the AUC/MIC values ofciprofloxacin is a good surrogate for bacteria eradication rate. It isalso suggested [Firsov et al, 1998] that the correlation between theantimicrobial effects of ciprofloxacin and AUC/MIC is independent oforganism species, gram positive or gram negative. The bacteriaeradication rate increases with time and is correlated with the AUC/MICvalues (FIG. 3) for both gram positive and negative bacteria as shown ina literature study [Forrest et al, 1993(b)], which includes both typesof bacteria with a MIC range (0.008-0.4 μg/mL) covering that of anthrax.As the patient fatality occurs rapidly after the onset of anthrax, it iscritical to treat the patients with the ciprofloxacin regimens producingadequate AUC/MIC values. For the treatment regimens producingAUC/MIC<125, more than 60% of the anthrax-exposed patients may remainculture-positive after 10 days, which is not acceptable for treating thefatal disease, of which the average onset-to-death time is 3 days.Literature data [Forrest et al, 1993(b); Craig, 1998; Bedos, 1998] alsoshow that the survival rates of human and animals infected with otherbacteria are correlated to AUC/MIC values of ciprofloxacin and otherfluoroquinolones that are used for treating the infections.

The relationship between AUC/MIC values and the percentage ofanthrax-exposed patients with blood culture remaining positive on day iafter the treatment initiation can be expressed by the followingempirical equation:

Percentage of culture-positive patients on day i=CP _(<125,i)% ifAUC/MIC<125

Percentage of culture-positive patients on day i=CP _(125-250,i)% if125<AUC/MIC<250

Percentage of culture-positive patients on day i=CP _(250,i)% ifAUC/MIC>250  (2)

where day 1 is the first day of treatment.

D. Correlation between Pharmacodynamics Marker, Patient Characteristics,and Dose Regimen

An investigation further utilized various patient characteristics topredict the pharmacodynamics markers of ciprofloxacin. The patientcharacteristics include age, gender, body weight, ethnicity, serumcreatinine, and creatinine clearance. The correlation betweenpharmacodynamic marker, patient characteristics and dose regimen, can bedescribed by population pharmacokinetic models or other empiricalexpressions.

The following two-compartment model ciprofloxacin pharmacokinetics wasdeveloped based on literature data [Forrest et al, 1993(a), Breilh etal, 2001; Terzivanov et al, 1998; Levey et al 1999; Lewis et al, 2001;Jones et al, 1998]: $\begin{matrix}{{{\frac{C_{1}}{t} = {{{- \left( {k_{el} + k_{12}} \right)}C_{1}} + {k_{21}C_{2}}}},\quad {C_{1,i} = {{f \cdot C_{1}} + ɛ_{{cl},i}}}}{{\frac{C_{2}}{t} = {{k_{12}C_{1}} - {k_{21}C_{2}}}},\quad {C_{2,i} = {C_{2} + ɛ_{{c2},i}}}}{{k_{el} = \frac{{CL}_{t}}{V_{1}}},\quad {K_{12} = \frac{{CL}_{d}}{V_{1}}},\quad {K_{21} = \frac{{CL}_{d}}{V_{2}}}}{{V_{1} = {V_{1,{ty}} + \eta_{vl}}},{V_{2} = {V_{2,{ty}} + \eta_{v2}}},{{CL}_{d} = {{CL}_{d,{ty}} + \eta_{cld}}},{{CL}_{t} = {{CL}_{t,{ty}} + \eta_{clt}}}}{{{CL}_{t,{ty}} = {\left( {{\theta_{1} \cdot {CL}_{cr}} + \theta_{2}} \right) \cdot {BW}}},{V_{1,{ty}} = {\theta_{3} \cdot {BW}}},{V_{2,{ty}} = {\theta_{4} \cdot {BW}}}}{{CL}_{cr} = {{{func}\left( {{age},{gender},{{body}\quad {weight}},{ethnithity}} \right)} + \eta_{cclcr}}}} & (3)\end{matrix}$

where C₁ is the plasma concentration, C₂ is the concentration in theperipheral compartment, f is a factor accounting for oralbioavailability, k_(e1) is the elimination rate constant from thecentral compartment, k₁₂ and k₂₁ are the distribution rate constantsbetween the central and peripheral compartments, CL_(t) is the totalclearance, CL_(d) is the distribution clearance, V₁ is the centralcompartment volume of distribution, V₂ is the peripheral compartmentvolume of distribution, CL_(cr) is the creatinine clearance of thepatient and is a function of the patient's characteristics, BW is thebody weight of the patient, θ represents the covariate model parameter,η represents the between-subject variability, ε represents thewithin-subject variability and the residual error of the model, idenotes the individual values, and ty denotes the typical populationvalues.

The population-mean of a pharmacodynamic marker, such as AUC/MIC, can beestimated from Equation 3, given the patient characteristics of thepopulation. The population-distribution of the pharmacodynamic marker inthe typical population can also be estimated, based on thebetween-subject and within-subject variability. The Monte-Carlosimulation technique [Lee, 2001] can be used to estimate the populationdistribution of the pharmacodynamic marker. An example of the populationdistribution of AUC/MIC is shown in FIG. 4, where the patientpopulation, with age=30 year and body weight=70 Kg, is given 500 mg bidciprofloxacin oral regimen. The distribution of the steady-statepharmacodynamic marker AUC_(24h)/MIC for 1000 such patients is shown inthe plot. The percentage of the patients with AUC/MIC<125 following thedose regimen can be calculated as the ratio of the area under the curvewhere AUC/MIC<125 (the shaded area in the plot) to the total area underthe distribution curve. Similarly, the percentages of the patients with125<AUC/MIC<250 or AUC/MIC>250 can be estimated from the distributionprofile in FIG. 4. The patient distribution with various AUC/MIC valuescan be expressed by the following empirical equation:

Percentage of patients with AUC/MIC<125=P _(AUC/MIC<125)%

Percentage of patients with 125<AUC/MIC<250=P _(125<AUC/MIC<125)%

Percentage of patients with AUC/MIC>250=P _(AUC/MIC>125)%  (4)

The percentage of patients with positive culture after the treatmentinitiation for patient groups with different AUC/MIC is shown in FIG. 3.The overall percentage of patients with positive culture after aspecific time, day i, following the treatment initiation can then becalculated as follows: $\begin{matrix}{{\% \quad {patients}\quad {with}\quad {positive}\quad {culture}\quad {on}\quad {day}\quad i} = {\sum\limits_{{j = 1},3}\quad {P_{j} \cdot {CP}_{j,i}}}} & (5)\end{matrix}$

where j=1 to 3, corresponding to AUC/MIC<125, 125<AUC/MIC<250, andAUC/MIC>250 respectively, and CP and P are defined in Equations (2) and(4).

E. Correlation Between Patient Survival, Bacteria Eradication Rate, andAntibiotic Regimen

The probability of patient survival on day i into the ciprofloxacintreatment, which is initiated on day j after the disease onset, can bedetermined based on the following Equation: $\begin{matrix}{{\% \quad {surviving}\quad {and}\quad {culture}\quad {positive}\quad {patients}\quad {in}\quad {Group}\quad k\quad {on}\quad {day}\quad i\quad {after}\quad {treatment}\quad {initiation}} = {{{SCP}_{i,k}\quad \%} = {{P_{k} \cdot {SCP}_{{i - 1},k}}\frac{{CP}_{i}}{{CP}_{i - 1}}\frac{S_{i + j}}{S_{i + j - 1}}}}} & (6) \\{{\% \quad {death}\quad {occur}\quad {in}\quad {Group}\quad k\quad {on}\quad {day}\quad i\quad {after}\quad {treatment}\quad {initiation}} = {{D_{i,k}\quad \%} = {{{P_{k} \cdot {SCP}_{{i - 1},k}}\frac{{CP}_{i}}{{CP}_{i - 1}}S_{i + j - 1}} - \frac{S_{i + j}}{S_{i + j - 1}}}}} & \quad \\{{{Overall}\quad {survival}\quad {rate}\quad {for}\quad {treatment}\quad {initiated}\quad {on}\quad {day}\quad j\quad {after}\quad {disease}\quad {onset}} = {S_{j - 1} - {\sum\limits_{k}\quad {\sum\limits_{i}\quad D_{i,k}}}}} & \quad\end{matrix}$

where S, CP, and P are defined in Equations 1, 2, and 4 respectively, kdenotes the patients group defined by AUC/MIC ranges in Equations 2 and4, Cp_(i)/Cp_(i−1) is the ratio of patients remaining culture positivefrom day i−1 to i after treatment initiation, and S_(i+j)/S_(i+j−1) isthe ratio of culture-positive patients (inactive control) remainingalive from day i+j−1 to i+j after disease onset. The basic assumptionfor the above equation is that the probability of survival for aculture-positive patient on day (i+j) after disease onset is the same asthe survival rate of the control group without effective treatment onthe same day after disease onset. The assumption is based on theobservation that even a small amount of bacteria level (10 cfu/mL)[Friedlander et al, 1993] may cause death in animals. Bacteremia atlevels of 10-10⁵ cfu/mL was present in the control monkeys before theirdeaths due to anthrax [Friedlander et al, 1993].

F. Survival Rate by Patient Characteristics, Dose Regimens, andOnset-to-treatment Time

An investigation utilized the overall survival model described above(Equations 1-6) to estimate the survival rates of anthrax-exposedpatients as a function of patients characteristics and treatmentinitiation days. The overall survival rate on day 10 after disease onsetwas estimated as a function of the onset-to-treatment time (0-5 days)for different patient populations defined by their gender, age, and bodyweight (Table 1). Six dose regimens (625 mg to 1500 mg twice daily) ofciprofloxacin were investigated. All patient populations included in theinvestigation were assumed to be healthy before contracting anthrax,with normal kidney and liver functions, and normal blood pressure. Basedon the result, the survival rate is slight better in the femalepatients. From the survival data of the controlled patients (FIG. 1)[Meselson et al, 1994], most of the anthrax-exposed patients withoutproper treatments died within 10 days after the disease-onset;therefore, the ciprofloxacin regimen should be given for at least 10days. In addition, some patients may have disease onset over 60 daysafter the initial exposure to the anthrax spores; therefore, theciprofloxacin treatment can be given to the patients up to 120 days toensure complete eradication of the anthrax bacteria.

Based on the results shown in Table 1, it is discovered that thesurvival rate of anthrax-exposed patients can be significantly improvedin some populations with a ciprofloxacin regimen between 625 mg and 1500mg twice daily, compared with the 500 mg twice daily regimen. Forexample, for a male patient with an age between 20-39 year and a bodyweight between 110-150 kg, a ciprofloxacin regimen between 625 mg to1000 mg gives a significant better treatment effect than the 500 mgtwice daily regimen. The survival rate of anthrax-exposed patients underprophylaxis treatment is represented by the survival rate that isestimated by assuming the onset-to-treatment time is 0 day.

G. Verification of the Model Predictability of Anthrax Patient SurvivalRates.

The survival rates of a typical patient population (typical patientswith age between 40-79 year, and body weight between 50-90 Kg) estimatedby the aforementioned method, described in sections B-F, are comparedwith the historical survival data of anthrax-exposed patients (FIG. 5).The historical data shown in FIG. 5 consist of the overall survival dataof the victims in the US bioterrorism attacks (FIG. 1) with the averageonset-to-treatment time=4 days (FIG. 2); the overall survival rate ofthe patients in the Sverdlovsk outbreak (FIG. 1), assuming no effectivetreatment was given (onset-to-treatment>8 days); the survival rate ofmonkeys (treatment initiated on day 0) [Friedlander et al, 1993] withcomparable ciprofloxacin plasma concentration to human; and the 6-pointrunning average of the US data. The running average of survival rate andonset-to-treatment time for every 6 patients in the US 2001 anthraxoutbreak was calculated, with the patients ranked in the order of theonset-to-treatment time.

The estimated survival rate of the typical population using the overallsurvival model (Equations 1-6) are consistent with the historical data(FIG. 5). The consistency between the estimated and the observedsurvival rates validated the method used in the investigations thatleaded to the discoveries in the present invention.

H. Safety of Ciprofloxacin Treatment

The safety of ciprofloxacin treatment was evaluated by examining severalpharmacokinetic markers for safety, including Cmax and AUC, where Cmaxwas the maximum plasma concentration of ciprofloxacin following a doseof the drug, and AUC was the area under the plasma concentration-timecurve of ciprofloxacin following a dose of the drug. These biomarkerswere determined by the population model (Equation 3) as a function ofdose regimen of ciprofloxacin and patient characteristics. The values ofthe safety biomarkers should fall within the normal range of theciprofloxacin therapy. If the biomarkers fall outside the upper bound ofthe normal a range, adverse events associated with ciprofloxacin mayoccur more than normal.

It was discovered that the following ciprofloxacin regimens are safe:

(a) a regimen up to 750 mg twice daily in patients with an age between12-19 year and a body weight between 50-70 kg,

(b) a regimen up to 1000 mg twice daily in patients with a body weightbetween 70-110 kg,

(c) a regimen up to 1250 mg twice daily in patients with a body weightbetween 110-150 kg.

TABLE 1 The overall survival rate of anthrax patients on day 10 afterthe disease onset. Onset-to- Survival Rate (%) Patient treatment 500 mg625 mg 750 mg 1000 mg 1250 mg 1500 mg Characteristics (day) bid bid bidbid bid bid Gender = M 0 84% 88% 90% 91% 92% 92% Age = 12-19 y 1 81% 87%88% 90% 91% 91% BW = 50-70 kg 2 75% 80% 82% 84% 85% 85% 3 65% 70% 71%73% 74% 74% 4 46% 48% 49% 50% 50% 50% 5 36% 38% 38% 38% 39% 39% Gender =M 0 75% 81% 84% 89% 90% 91% Age= 12-19 y 1 71% 79% 82% 87% 89% 90% BW =70-110 kg 2 64% 72% 75% 81% 83% 84% 3 56% 62% 65% 70% 72% 73% 4 41% 44%46% 48% 49% 50% 5 34% 35% 36% 38% 38% 38% Gender = M 0 64% 70% 77% 83%87% 89% Age = 12-19 y 1 58% 65% 73% 81% 85% 88% BW = 110-150 kg 2 51%58% 66% 74% 79% 81% 3 44% 50% 57% 64% 68% 71% 4 35% 38% 42% 45% 47% 49%5 30% 32% 34% 36% 37% 38% Gender = M 0 87% 90% 91% 92% 92% 92% Age =20-39 y 1 86% 88% 90% 91% 91% 91% BW = 50-70 kg 2 79% 82% 84% 84% 85%85% 3 69% 71% 73% 74% 74% 74% 4 48% 49% 50% 50% 50% 50% 5 37% 38% 38%39% 39% 39% Gender = M 0 80% 85% 88% 91% 91% 92% Age = 20-39 y 1 77% 83%86% 89% 90% 91% BW = 70-110 kg 2 70% 76% 79% 83% 84% 84% 3 61% 66% 69%72% 73% 74% 4 44% 46% 48% 50% 50% 50% 5 35% 36% 37% 38% 38% 39% Gender =M 0 70% 75% 80% 87% 89% 90% Age = 20-39 y 1 65% 71% 77% 85% 88% 89% BW =110-150 kg 2 58% 64% 71% 79% 81% 83% 3 50% 55% 61% 68% 71% 72% 4 38% 41%44% 47% 49% 49% 5 32% 33% 35% 37% 38% 38% Gender = M 0 88% 91% 91% 92%92% 92% Age = 40-59 y 1 87% 89% 90% 91% 91% 91% BW = 50-70 kg 2 80% 83%84% 85% 85% 85% 3 70% 72% 73% 74% 74% 74% 4 48% 50% 50% 50% 50% 50% 537% 38% 38% 39% 39% 39% Gender = M 0 86% 88% 91% 92% 92% 72% Age = 40-59y 1 84% 87% 89% 90% 91% 67% BW = 70-110 kg 2 78% 80% 83% 84% 85% 60% 367% 70% 72% 73% 74% 52% 4 47% 48% 50% 50% 50% 39% 5 37% 38% 38% 39% 39%33% Gender = M 0 72% 78% 83% 87% 90% 91% Age = 40-59 y 1 67% 74% 81% 86%88% 90% BW = 110-150 kg 2 60% 68% 74% 79% 82% 84% 3 52% 58% 64% 69% 71%73% 4 39% 42% 45% 48% 49% 50% 5 33% 34% 36% 37% 38% 38% Gender = F 0 86%89% 91% 92% 92% 92% Age = 12-19 y 1 84% 87% 89% 91% 91% 91% BW = 50-70kg 2 78% 81% 83% 84% 85% 85% 3 68% 70% 72% 74% 74% 74% 4 47% 49% 50% 50%50% 50% 5 37% 38% 38% 39% 39% 39% Gender = F 0 78% 84% 87% 90% 91% 92%Age = 12-19 y 1 75% 82% 85% 88% 90% 90% BW = 70-110 kg 2 68% 75% 78% 82%84% 84% 3 59% 65% 68% 71% 73% 74% 4 43% 46% 47% 49% 50% 50% 5 34% 36%37% 38% 38% 39% Gender = F 0 67% 73% 80% 86% 88% 90% Age = 12-19 y 1 62%69% 77% 83% 87% 89% BW = 110-150 kg 2 54% 62% 70% 77% 80% 82% 3 47% 53%61% 67% 70% 72% 4 36% 40% 44% 47% 48% 49% 5 31% 33% 35% 37% 37% 38%Gender = F 0 90% 91% 92% 92% 92% 80% Age = 20-39 y 1 89% 90% 91% 91% 91%78% BW = 50-70 kg 2 83% 84% 85% 85% 85% 71% 3 72% 73% 74% 74% 74% 61% 449% 50% 50% 50% 50% 44% 5 38% 38% 39% 39% 39% 35% Gender = F 0 80% 85%88% 91% 92% 92% Age = 20-39 y 1 78% 83% 87% 89% 90% 91% BW = 70-110 kg 271% 77% 80% 83% 84% 84% 3 61% 66% 70% 72% 73% 74% 4 44% 47% 48% 50% 50%50% 5 35% 37% 37% 38% 38% 39% Gender = F 0 70% 77% 82% 87% 90% 91% Age =20-39 y 1 65% 73% 80% 85% 88% 90% BW = 110-150 kg 2 58% 67% 73% 79% 82%83% 3 50% 57% 63% 68% 71% 73% 4 38% 42% 45% 47% 49% 50% 5 32% 34% 36%37% 38% 38% Gender = F 0 89% 91% 92% 92% 92% 92% Age = 40-59 y 1 87% 90%90% 91% 91% 91% BW = 50-70 kg 2 81% 83% 84% 85% 85% 85% 3 70% 73% 73%74% 74% 74% 4 48% 50% 50% 50% 50% 50% 5 38% 38% 39% 39% 39% 39% Gender =F 0 87% 89% 91% 92% 92% 73% Age = 40-59 y 1 85% 87% 90% 90% 91% 69% BW =70-110 kg 2 78% 81% 83% 84% 85% 62% 3 68% 70% 73% 73% 74% 53% 4 47% 49%50% 50% 50% 40% 5 37% 38% 38% 39% 39% 33% Gender = F 0 73% 79% 84% 88%90% 91% Age = 40-59 y 1 69% 76% 81% 86% 89% 90% BW = 110-150 kg 2 62%69% 75% 80% 83% 84% 3 53% 60% 65% 69% 72% 73% 4 40% 43% 46% 48% 49% 50%5 33% 35% 36% 37% 38% 38%

I. An Example

The following example is included to demonstrate the embodiments of theinvention for one of many applications. Those of skill in the artshould, in light of the present disclosure, appreciate that many changescan be made in the specific embodiments that are disclosed and stillobtain a like or similar result without departing from the spirit andscope of the invention.

The present invention provides a method for optimizing ciprofloxacintreatment of anthrax-exposed patients according to the patient'scharacteristics. The invention is primarily based on the discovery ofsurvival rates in different patient populations following different doseregimens of ciprofloxacin, as listed in Table 1.

An example of survival rates in anthrax-exposed patients on day 10 afterthe disease onset is shown in FIG. 6. Survival rates of three groups ofmale patients were included in this example, with body weight equal to60 Kg, 90 Kg, and 130 Kg respectively, and age equal to 30 year. Fourdifferent dose regimens of ciprofloxacin were given to the patients:500, 750, 1000, and 1250 mg twice daily (bid). The results from thisexample show that the 60-kg group slightly benefits by an increase indose from 500 mg to 750 mg bid, while raising the dose further does notincrease the survival rate. The 90-Kg group continuously benefits fromincreasing dose regimens, with the mortality rate on day 0 drops by 2folds from 20% following 500 mg bid to 10% following 1000 mg bidregimens. The increase in the survival rate of the 130-kg group withincreasing dose is even dramatic. The result also indicates a trend ofreducing overall survival rate with increasing onset-to-treatment time.The severely ill patients with long onset-to-treatment time mayparticularly benefit from high ciprofloxacin doses.

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Which is claimed is:
 1. A method for selecting an oral ciprofloxacinregimen that produces treatment effects in survival rate significantlybetter than a 500 mg twice daily regimen of the same drug forpost-exposure prophylaxis treatment or post-disease-onset treatment ofanthrax in an anthrax-exposed patient, comprising selecting a regimenwherein: (a) said patient has an age between 12-19 year and a bodyweight between 50-70 kg, and said selected oral ciprofloxacin regimen isa dose between 625 mg to 750 mg given twice daily for a treatment periodof 10 to 120 days; or (b) said patient has a body weight between 70-110kg, and said selected oral ciprofloxacin regimen is a dose between 625mg to 1000 mg given twice daily for a treatment period of 10 to 120days; or (c) said patient has a body weight between 110-150 kg, and saidselected oral ciprofloxacin regimen is a dose between 625 mg to 1250 mggiven twice daily for a treatment period of 10 to 120 days; or (d) saidpatient has an age between 12-39 year and a body weight between 70-110kg, and said selected oral ciprofloxacin regimen is a dose between 625mg to 1000 mg given twice daily for a treatment period of 10 to 120days.
 2. A method for selecting an oral ciprofloxacin regimen thatproduces a treatment effect in survival rate at least 5% better than a500 mg twice daily regimen of the same drug for post-exposureprophylaxis treatment of anthrax in an anthrax-exposed patient,comprising selecting a regimen wherein: (a) said patient has an agebetween 12-19 year and a body weight between 50-70 kg, and said selectedoral ciprofloxacin regimen is a dose between 750 mg to 1000 mg giventwice daily for a treatment period of 10 to 120 days; or (b) saidpatient has an age between 12-39 year and a body weight between 70-110kg, and said selected oral ciprofloxacin regimen is a dose between 625mg to 1000 mg given twice daily for a treatment period of 10 to 120days; or (c) said patient has a body weight between 110-150 kg, and saidselected oral ciprofloxacin regimen is a dose between 625 mg to 1250 mggiven twice daily for a treatment period of 10 to 120 days.
 3. A methodfor providing post-exposure prophylaxis treatment or post-disease-onsettreatment of anthrax in a patient with an oral ciprofloxacin regimenthat is safe and produces treatment effects in survival ratesignificantly better than a 500 mg twice daily regimen of the same drug,comprising providing a regimen wherein: (a) said patient has an agebetween 12-19 year and a body weight between 50-70 kg, and said oralciprofloxacin regimen is a dose between 625 mg to 750 mg given twicedaily for a treatment period of 10 to 120 days; or (b) said patient hasa body weight between 70-110 kg, and said oral ciprofloxacin regimen isa dose between 625 mg to 1000 mg given twice daily for a treatmentperiod of 10 to 120 days; or (c) said patient has a body weight between110-150 kg, and said oral ciprofloxacin regimen is a dose between 625 mgto 1250 mg given twice daily for a treatment period of 10 to 120 days;or (d) said patient has an age between 12-39 year and a body weightbetween 70-110 kg, and said oral ciprofloxacin regimen is a dose between625 mg to 1000 mg given twice daily for a treatment period of 10 to 120days.
 4. A method for providing post-exposure prophylaxis treatment orpost-disease-onset treatment of anthrax in a patient with an oralciprofloxacin regimen that is safe and produces a treatment effect insurvival rate at least 5% better than a 500 mg twice daily regimen ofthe same drug, comprising providing a regimen wherein: (a) said patienthas an age between 12-19 year and a body weight between 50-70 kg, andsaid oral ciprofloxacin regimen is a dose between 750 mg to 1000 mggiven twice daily for a treatment period of 10 to 120 days; or (b) saidpatient has an age between 12-39 year and a body weight between 70-110kg, and said oral ciprofloxacin regimen is a dose between 625 mg to 1000mg given twice daily for a treatment period of 10 to 120 days; or (c)said patient has a body weight between 110-150 kg, and said oralciprofloxacin regimen is a dose between 625 mg to 1250 mg given twicedaily for a treatment period of 10 to 120 days.
 5. The method of any oneof claims 1-4, wherein said patient is male or female.
 6. The method ofany one of claims 1-4, wherein said patient has a normal kidneyfunction.
 7. The method of any one of claims 1-4, wherein said patienthas a normal liver function.
 8. The method of any one of claims 1-4,wherein said patient has a normal blood pressure.
 9. The method of anyone of claims 1-4, wherein said patient is otherwise healthy beforeexposed to anthrax.